Future directions

DLB is a complex disease process that affects a number of different neuronal systems. Although the mechanisms are not entirely understood, it seems that the likely pathological substrate is aggregates of synaptic protein α synuclein resulting in neuronal dysfunction and eventual loss. Subcortical structures seem more vulnerable with a variety of functional and structural imaging changes observed, in a differing pattern to that seen in AD. In order to develop disease biomarkers we need to establish a link between the clinical features observed and the in vivo imaging changes.

Structural imaging

In DLB, cortical areas are potentially affected by a combination of impaired neuronal projections from subcortical structures and directly by varying degrees of AD pathology. One method to explore this further would be to investigate the differing patterns of structural covariance between DLB and AD.

Chapter 7 Conclusions and future studies Longitudinal imaging studies can also assist in providing insight into more susceptible regions of change in DLB, and how the pattern may differ from AD. The rate of atrophy also has potential as an outcome measure in therapeutic trials and establishing a link between atrophy rate and a clinically significant outcome. In the first instance, a longitudinal study using VBM-DARTEL method of analysis comparing the regional atrophy rate in AD and DLB would be of interest.

Multi-modal imaging

Another approach would be to incorporate information from differing imaging modalities. Areas of interest would include the posterior (parieto-occipital) and thalamic areas. These are key areas involved in visuo-perceptual and attentional function and our DTI findings in DLB indicate that further analysis is warranted. In particular, using a ROI method, data from diffusion and perfusion imaging techniques could be combined in a multivariate model along with clinical variables, to better understand the in vivo functional changes in DLB. This could be investigated using SPECT or PET in combination with DT-MRI. However, the main advantages for multi-modal MRI studies combining structural imaging, DTI and perfusion (using arterial spin labelling) are that all data can be acquired during a single session and registration issues are less problematic.

Sub-group analysis

It is likely that there were varying degrees of associated AD pathology in the DLB group which may be reflected in the degree of episodic memory dysfunction and GM volume loss, particularly hippocampal atrophy. To provide more insight into the pathophysiological mechanisms of DLB it would be instructive to divide the DLB group on the basis of hippocampal volume, a surrogate measure of AD pathology and further review any patterns of DTI change in the DLB group with particular focus on the relationship with executive function tasks and motor symptoms. This has the potential to explore the imaging changes characteristic of DLB pathology without the effect of AD ‘diluting’ the differences between the groups.

Clinical aspects

Important aspects of clinical imaging studies that need to be considered are a well- defined patient group with robust methods for characterisation of the core clinical

features. Adequate and well validated methods for testing of attention and fluctuation, visual perception and motor features is of particular importance so that they can be used reliably as probes for correlation with imaging changes. In addition, dopamine transporter imaging, amyloid PET and genetic markers (e.g. ApoE4) would provide better characterisation of the groups.

Neuropathological correlational studies

Finally, neuropathological correlation studies are needed to assist in understanding the pathological substrates of imaging changes in DLB. This has been clearly demonstrated by others and has been central to our understanding of the basis of medial temporal atrophy and amygdala changes in DLB (Burton et al., 2011; Burton et al., 2009).

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